CA1277330C - Carbamate or urea derivatives, their preparation and pharmaceutical compositions comprising them - Google Patents

Abstract

ABSTRACT
A compound which is carbamate or urea derivative of general formula (I) (I) wherein X is hydrogen, halogen or methylthio, Y is oxygen or

Description

33~

"CARBAMATE OR UREA DERIVATIVES, THEIR PREPARATION AND
PHARMACEUTICAL COMPOSITIONS COMPRISING THEM"
The invention relates to novel carbamate and urea derivatives and their acid addition salts which are pharmacologically active as calcium antagonists.
According to the invention there is provided a compound which is a carbamate or urea derivative of general formula ~I) X ~ SCH3 N ~

O (IH2)n (I).

~CR2)m Y N

wherein X is hydrogen, halogen or methylthio, Y is oxygen or -NH, R is Cl-C4 alkyl, Rl is hydrogen, one or two halogen atoms or trifluoromethyl groups, a methyl group, a methoxy group, a cyano yroup, a nitro group, a methoxycarbonyl group, a methylenedioxy group l-inked to two adjacent carbon atoms of the benzene ring to ~; 15 which it is attached, or a fused benzo group forming an a-naphthyl or ~-naphthyl group with the benzene ring to : which it is attachedj R2 is a linear or branched C1-C8 alkyl or alkenyl group optionally substituted with halogen atoms or a methoxy group, a cyclopropylmethyl group, or a phenyl group optionally substituted with one or two halogen atoms or methyl groups, 7733~

n is 1 or 2, and - m is 2 or 3, or an addition salt thereof with a pharmacologically acceptable acid.
The compounds of the invention can thus be presented in the states of free bases, or as addition salts with pharmacologically acceptable acids.
The preferred compounds are those of formula (I) in which n and m are each 2 and Y is an oxygen atom and their acid addition salts.
The compounds of the invention may be prepared for example, by the process illustrated by the scheme on the following page.
In this process a 2-methylthiobenzenamine of formula (II) (in which X is as defined above) is condensed with a benzaldehyde of formula (III) (in which Rl is as ; defined above), suitably in a solvent such as benzene under reflux, and preferably in the presence of para-toluenesulphonic acid, to provide an imine of formula (IV) which is then hydrogenated, for example by means of sodium cyanoborohydride, suitably in a solvent such as methanol and preferably at room temperature. The amine of formula (V) thereby obtained is reacted with an acid chlorine of formula (VI) (in which n is as defined above), suitably in a solvent such as ethyl ether and preferably at room t7t~33~ .

SCHEME
,~,~ SCH3 X--W~ (II3 NH2 X ~S~H3 ~ IV ) --- ~N//~

R~
¦NaBH3CN

~S~3 ~ SC~3 X ~ ¦1 5VII ) X ~ ~ 5~J) ~N --~- Rl (VI ) N _ 0~5 CH2 ~ ~J
Cl . N~2 ~H2)m ~VIII) : ~N
R R

X ~CH3 (~X3 ~5~3 ~Rl o - ~ 2)~ = f~23~
~N o r P~2-~CO 0~ N
~c~2 m r ~

~ \~ R2 ~R \'~R

~Z7~733~

temperature and in the presence of a base such as potassium carbonate. The chloride of formula (VII ) thereby obtained is reacted with a diamine of Eormula (VIII) (in which R and m are as defined above), suitably in a solvent such as dimethylformamide and preferably at room temperature and in the presence of potassium iodide, to provide a compound of formula (IX) which is reacted with, when Y is to b~ oxygen, a chloroformate of formula R2--O-CO-Cl (in which R2 is as defined above), suitably in a solvent such as ethyl ether and preferably at room temperature and in the presence of a strong base such as sodium hydroxide, or with, when Y i~ to be ~NH, an isocyanate o~ formula R2-NC0 (in which R2 is as defined above), suitably in a solvent such as dichloromethane and preferably at room temperature, to provide a compound of formula (I). The compound of formula (I) can be converted, if desired, into an addition salt with a pharmacologically acceptable acid in manner known psr se.
The following Example describes in detail a procedure for preparing the compounds of the invention.
The Table which follows the Example illustrates the structures and physical properties of some other compound~. The structures of the compounds thus described were confirmed by microanalyses and IR and NMR spectra Example 2 Methylpropyl ~2-(dimethylamir,o)ethyl~[2-~2-~methyl-thio)-phenyl][(3-trifluoro~ethylphenyl)methyl~amino}-2-]
oxoethyl -carbamate 1. 2-tMethylthio~-N-{~3-~tri~luoromethyl~phenyl3-~ethylene}ben~enamine.

A mixture of 25 9 (0.174 mole) of 2~methylthio-benzenam;ne and 25.06 ml ~0~174 mole) of 3-trifluoromethyl-~2~733~

benzaLdehyde in 250 ml of benzene is heated under reflux in the presence of 0.3 9 of para-toluenesulphonic ac;d for 1 hour, the water formed b~eing removed by means of a Dean and Stark apparatus.
The ben~ene is evaporated off and the oily residue used without further treatment in the following stage.
2~ 2-(Methylthio)-N-{[3-(trifluoromethyl)phenyl]-methyl}benzenamide.
The residue from the above stage is dissolved in 300 mL of methanol, and 13.15 9 of sodium cyanoborohydride are added gradually while the mixture is stirred. When the reaction is co~plete, the pH is adjusted to 6 ~ith acetic ac;d and the solvent is then driven off.
; The res;due is taken up with ether and sodium bicarbonate and the organic phase is separated, dried and evaporated. The residue is distilled at 135C under approximately 13 Pa. 35.7 9 of amine are collected.

3. 2-Chloro-N-l2-(methylthio)phenyl~-N-{t3-(trifluoro-methyl)phenyl~methyl}acetamide.
A mixture of 10 9 tO.0337 mole) of the amine pre-; pared above, 5.35 ml ~O.Ob7 mole) of chloroacetyl chlor-ide and 40 9 of potassium carhonate in 250 ml of ether ;s stirred at room temperature for 5 hours.
The ;norganic products are separated by filtra-tion, the filtrate is wa~hed wi~h sodium bicarbonate and ther, u;th ~ater, and the organic phase ;s dried and evap-orated. There remain 12.57 9 of res;due which is used ' 3~

~ithout further treatment in the following stage.

4. 2-l2-(Dimethylamino)ethyl]amino-N-~2-(methylthio)-phenyl]-N-{C3-ttrifluoromethyl)phenyl]methyl}acetamide.
T~he residue from the above stage is dissolved in S 150 ml of dimethylformamide, and 11.07 ml (0~1 mole) of N~N-dimethyl-1,2-ethylenediamine and a spatula-tipful of potassium iodide are added.
The mixture is stirred at room temperature over-night, the solvent then evaporated off, the residue taken up with sodium bicarbonate and ether and the ether phase separated, dried and evaporated. There remain 12.5 g of ~ crude product which are used w;thout further treatment ; in the following stage.
`~ S~ 2-Methylpropyl C2-(dimethylamino)ethyl][2-{C2-(methylthio)phenyl~3-trifluoromethylphenyl)methyl]-amino}-2-oxoethyl~carbamate.
3 9 (0.007 mole~ of the produc~ of the above stage are dissolved in 50 ml of ether, 25 ml of ~ater are added and then, ~hile the pH is monitored, caustic soda is added unt;l ~he pH ;s 12.5 to 130 ~ 1.8 ml (0.014 mole) ~f isobutyl chloroformate are ; then added drop~ise, the pH being ma;ntained by adding sodium hydroxide.
Stirring is cont;nued at room temperature for 10 0inutes, and the organ;c phase ;s then separated, dried and evaporated. The residue is purified by chromatography on silica, eluting with a 99:1 mixture of methanol and ~ :~

~LZ~7~33~) ether. 2 g of pure base are finally collected. The oxa-late is prepared by dissolving the base and a stoichio-metric amount of acid in a minimum of ethanol, and iso-lating the sal~ which crystallizes.
S Melting point: 133C.

:
'~ ' ~l277331~

Table X~ SCH3 N~
~R
O ( ~ n H2)m (I) Y N

N X R~ Y R2 R n base M p;
. . .~ , _ . _ _ ~
1 H H iC4Hg CH3 1 2 46 134 ~:~. 2 H 2-C1 iC4Hg CH3 1 2 46 137.5 3 H 3-C1 0 iC~Hg CH3 1 2 46 126 ~:~ 4 H 6-F iC4Hg CH3 1 2 46 142.5 5 H 2,6-C1z iC4Hg CH3 1 2 46 lS9 6 H 4-CH3 i~4H9 ~H3 1 2 46 140 7 H 2-CN 0 iC~Hg . CH3 1 2 46 lS5,5 8 H ~ 4-CN iC4H9 CH3 1 2 46 141.5 9 B 2-CF3 CH3 . CH3 1 2 46 141-143 ~; 10 H 2-CF3 iC4Hg ~H3~ 1 2 46 135-136 `:~ 11 ~ 3-CF3 CH3 CH3 1 2 46 145 : 12 H 3-~F3 CH2C13 CH3 1 2 46 122-123 13 H 3-CF3 iC4Hg CH3 1 2 08 134-135 14 H 3-CF3 tC4Hg CH3 1 2 46 167-169 15 H 3-CP3 iCsHll C~3 1 2 ¦ 46 116-lI8 16 ~ 3-~3 0 C~2-tC4~g c~3 1 2 ~6 14S-146 17 H 3-CF3 CH(C2H5~2CH3 1 2 46 137-138 : 18 H 3-C~3 CH~CH3)-1C3H7 CH3 1 2 46 134-135 19 ~ 3-CF3 O W~ ~C~g CH3 1 _ 46 _ _ ' ~2~7~33~
_ 9 _ TabLe lcontinued) _ . _. . _ _ _ N~ X Rl Y R2 R ~ m Salt (C;
_ _ . ~ __ _ . _ I

21 ~ 3-OCH20-4 CH3 CH3 1 2 46 138 22 H 3-OOH20-4 iC4H9 CH3 1 2 10 140-143 23 H ~-ClOH7 O iC~Hg CH3 1 2 46 153 24 H ~-CIOH7 iC4~ CH3 1 2 46 153 25 H 3-CF3 iC4Hg nC3H7 1 2 46 78-79 26 H 3-OCB~0-4 CH3 DC3%7 1 2 46 116-118 27 H 3-CF3 CH3 nC3H7 1 2 ~6 80-82 28 H 3-0C~20-4 i~4Hg nC3H7 1 2 46 122-124 29 H 3-~F3 iC4~9 C~3 2 2 00 Oil 30 H 3-CF3 ~C4H9 CH3 1 3 00 Oil 31 ~ 3,4-C12 ~C4~9 c~3 1 2 46 137.5 32 h 2-OC~3 ~C4H9 CH3 1 2 46 128-130 33 H 3-CF3 4-Cl iC4Bg CH3 1 2 08 116 34 H 3-CP3 6-Cl iC4Hg OH3 1 2 OB 123-125 35 H 3-CF3 4-F iC4h3 CH3 1 2 08 126-127 36 ~ 2-F iCb~g C~3 1 2 08 134-135 37 H 4-CL iC4Hg CH3 1 2 C8 154-155 3~ H ~s-C12 iC4Hg C~3 1 2 08 156 39 ~ 2-C1 6-F O iO~g CH3 1 2 46 148 40 H 2-N~2 iC4Hg C~3 1 2 46 149 ~1 B 2-CH3 iC4~9 C~3 1 2 46 123 ~2 ~ 4-C02C~3 ~4H9 C~3 1 2 46 156-157 4~ ~ 4-C~3 . iC4~9 C83 1 2 08 134-136 44 ~ 3-CF3 C~(lC3H7~2 ~H3 1 2 46 133-134 45 ~ 3-~F3 CH(lC3H7)(~2~5) CH3 1 2 ~6 129-130 46 ~ 3-~3 O C~(~C4Hg~(~H3~ ~83 1 2 ~ 117-118 47 ~ 4~~3 ~2C(C~3)3 ~ 1 2 ~0 12~.5-12 48 ~ 3~~Y3 ~C3~7 c~3 1 2 46 134 49 ~ 3-~3 o ~2~(C~3)S~2 ~a3 1 2 46 1~8,5 50 ~ ~ 3-GP3 CH2CH:~2 ~3 1 2 46 143 51 ~ 4-C~3 lC3H7 C~3 1 2 46 142.5-143.5 52 ~ 4-CF3 CH2C(CH3):C~2 C~3 1 2 4~ 142 53 a 4-CF3 O C~2C~2-1C3n7 ~3 1 2 46 ororpho~s ~733~

Table (continued) _ _ ~ _ _ _ _ . , ~ X Rl Y R2 R n m Saltl M.p.
_ . _ __ . _ _ ~ base (C) 55 H 4-C~3 tC4Hg CH3 1 2 46 147-147,5 56 H ~-CF3 C~2-Cc3H5 CH3 1 2 46 137.5-139~5 : 57 H 4-CF3 CH(iC3~7)(CH3) CH3 1 2 46 142-143 5B H 3-CF3 CH(c2Hs)(c5Hll) CH3 1 2 00 Oil 59 H 3-CF3 C~(CH3)(C4Hg) CH3 1 2 00 Oil 60 H 3-CF3 CH2CH20CH3 C~3 1 2 46 126.5 61 8 3-C~3 C~(cH3)(c2H5) CH3 1 2 46 lb4,5 ; 62 H 3 c~3 CH(C3H7)(iC3H7) CH3 1 2 46 131.5 63 H 3-CF3 nCgH17 CH3 1 2 00 Oil : 64 3-Cl 4-Cl iC4Hg C%3 1 2 46 86.5 65 4-Cl 4-CF3 iC4H9 CH3 1 2 46 amorphous 66 3-Cl 4~~ i~4Hg CH3 1 2 46 120-121 67 3-Cl 2-~ iC4~9 CH3 1 2 46 131-132 : 68 5-Cl 4-CF3 iC4Hg C~3 1 2 46 144-145 69 6-SCH3 4-CF3 iC4~9 CH3 1 2 46 152 70 4-Cl 3-CF3 iC4Hg CH3 1 2 46 120 71 H 3-CF3 NH nc3H7 CH3 1 2 46 118-119 72 ~ 3-CF3 NH iC3H7 CH3 1 2 46 138-139 ~: 73 H 3-CF3 NH nc4H9 CH3 1 2 46 126 tdec3 74 ~ 3-CF3 NH c6~s CH3 1 2 46 132-133 75 H 3-CF3 NH C~H4-F~2~ CH3 1 2 00 126-127 : 08 160 (dec) 76 H 3-C~3 NH C6H4-F(2) CH3 1 3 46 146 :
: 77 ~ 3-C~3 NH C6H4-F(2~ CH3 2 2 46 168 78 H 4-C~3 NH ~6H3-~H3(2)-F(s~ c~3 1 2 46 143-144 . 79 H 4-CF3 : NH C6H3-CB3(2)-C1(6) C~3 . 1 2 46 143 : 80 H 4.C]F3 : NH ~6H3-F2(2,6) CR3 1 2 46 171~5-172 : 81 ~ 4~CF3 NH C6H3-C12(2,6) C~3 I 2 46 159-160 82 H 4-C.13 - C6H4-~(2) C~3 1 2 08 162 ~ 2~7 33 ~

Legend to the table "R1" column: ~-C10H7 and ~-C10H7 denote a-naphthyl and B-naPhthyl radicals, respectiveiy, formed by R1 and the benzene ring to which ;t ;s attached.
S R2 column: nC3H7~ iC3H7, C3Hs, nC4Hg, iC4Hg, tC4Hg sC4Hg~ iCsH11 and nCgH17 denote n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, isopentyl and n-octyl radicals, respectively. C6Hs, C6H4-Z(p) and C6H3-Z(p)-W(q) denote phenyl radicals, and phenyl radicals monosubst;tuted or disubstituted w;th Z
and/or W at the p- and q-positions, respectively.
"Salt/base" column: 00, D8, 10 and 46 denote the free -base, the fumarate, the hydrochlor;de and the oxalate, respectively.

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7733~

The compounds of the invention were subjected to pharmacolo~ical trials ~hich demonstrated their activity as a calciu~ antagonist.
The experimental protocol used is a variant of that of Godfraind and Kaba (Blockade or revPrsal of the contraction induced by calcium and adrenaline in depolar ized arterial smooth muscle, Br. J. Pharmac., (1969) 36, 54~-560).
The experiments uere carried out on sectional lengths of rabbit thoracic aorta. The animals, "Fauves de Bourgogne" of average weight 1.5 kg, ~ere sacrificed by cervical disLocation and exsangu;nation. The thoracic ~ aorta was rapidly re~oved and placed in an oxygenated ;~ Krebs bicarbonate medium (95% 2 ~ 5% C2) Sectional Lengths of aorta approximately 1 cm long ~ere prepared and mounted in 20-ml organ cells con-; taining oxygenated Krebs bicarbonate solution at pH 7.4 at 37C. Two U-shaped metal hooks having the same length as the sectional lengths were introduced into the bore of the latter. One of the hooks ~as attached to the base of the ce~L and~the other~ connected to an isome~ric strain ~auge (6rass FTo3), enables the contractile respon-ses of the sectional lengths of aorta eO be recorded, via a continuous preampl;fier (Grass 7P1), on a recording oscillograph (Gra,s 7~B). Th;s method has the advantage, compared ~ith spiral- or ring-shaped preparations, of preserving ~ore faithfully the structural integrity of ~ ~ ' .
' ~

~7733(~

the vessels and of recording only the radial components of the contractile responses, which represents the pheno-menon ~hichJ;s of interest from a functional standpoint (regulation of the arterial blood pressure). An initiaL
S tension of 4 9 ~as applied to lhe preparations Phenoxybenzamine (1 ~M~ and propranolol (1 ~M) were added to the different Krebs media in order to elim-inate the contractile responses linked to the activation of the vascular ~- and B-adrenergic receptors.
After one hour's stabilization in Krebs medium, the tension applied to the aortas was reduced to 2 9, and then, after a 30-minute waiting period, the preparations were incubated for about ten minutes ;n a calcium-free Krebs bicarbonate solution ;n the presence of EDTA
(200 ~M) and propranolol (1 uM). This solut;on was then replaced by 3 calcium-free depolari~ing ~potassium-rich) Krebs medium conta;ning propranolol (1 ~M). After 5 minutes, a single 1 mM concentration of calcium was added to this soLution and a 30-minute stabili~ation period was observed, this enabling the preparations to atta;n a stable contraction.
Cumulative doses of the test compounds ~ere then administered~every 30 minutes (~he time generally neaded for obtaining a stable condition) until there ~as complete disappearance of the contraction ;nduced by 1 mM calc;um, ; or alternatively until the concentration ~30 ~M) of teSt product W35 attained. At the end of the experiment~

,,, ~L27733~3 a supramaximal concentration of papaverine ~300 ~M) is administered in order to determine the maximum poss;ble relaxation of each preparation.
The absolute values ~;n grams) of the in;t;al contrac~;on (after 1 m~ calcium chloride~ and of the contraction after the d;fferent cumulat;ve concentrations of vasodilatory compounds were obtained, for each prepara-~ion, by difference ~ith the min;mal contraction observed 30 minutes after the final addit;on of 300 ~M papaverine.
The percentage decrease in the contraction, relat;ve to the contract;on ;nduced by 1 ~M calc;u~, was calculated for each dose of compound and each preparat;on, and the mean X + SEM of the ;ndiv;dual percentages ;s calculated.
The mean values obtained (weighted by the reciprocal of the standard error of the mean) were analysed using a mathematical sigmoid c~rve mode~, and the molar concen-~ tration inducing 50% relaxation of the response to calc;um ;~ (ECso) ~as calculated.
For the compounds of the ;nvention, the ECso values range from 0.6 ~M to 30 pM.
The compounds of the invention can be used forthe treatment of atl d;seases ;n which calcium antagonists ;~ .
can be used, such as angina pectoris, card;ac arrhythmia, hypertension, cardiomyopathy, myocardial protection of patients at r;sk of ;nfarction or who have suffered an infarction, cardiac arrest, stroke, mania, migraine~
Other trials have shown that the compounds of the ~.
' .

: .

~Z7733~

invention also inhibit platelet aggregation, and they may hence be used for the treatment of conditions which result therefrom.
Finally, trials perfor~ed on animals subjected to stress have shown that the compounds of the invention also have properties for combatting gastric or gastro-duodenal ulcers~
The compounds of the invention can be presented in any form suitable for oral or parenteral administra-tion, in combination with any suitable excipient, forexample in the form of tablets, gelatin capsules, cap-sules, solutions for oral administration or injectable solutions.
The daily dosage can range from 30 to 600 mg orally and from 0.06 ~o 180 mg parenterally.

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Claims (3)

1. A process for preparing a compound which is a carbamate or urea derivative of general formula (I) (I) wherein X is hydrogen, halogen or methylthio, Y is oxygen or , R is C1-C4 alkyl, R1 is hydrogen, one or two halogen atoms or trifluoromethyl groups, a methyl group, a methoxy group, a cyano group, a nitro group, a methoxycarbonyl group, a methylenedioxy group linked to two adjacent carbon atoms of the benzene ring to which it is attached, or a fused benzo group forming an .alpha.-naphthyl or .beta.-naphthyl group with the benzene ring to which it is attached, R2 is a linear or branched C1-C8 alkyl or alkenyl group optionally substituted with halogen atoms or a methoxy group, a cyclopropylmethyl group, or a phenyl group optionally substituted with one or two halogen atoms or methyl groups, n is 1 or 2, and m is 2 or 3, or an addition salt thereof with a pharmacologically acceptable acid, which process comprises condensing a 2-methylthiobenzenamine of formula (II) (II) (in which X is as defined herein), with a benzaldehyde of formula (III) (III) (in which R1 is as defined herein), to provide an imine of formula (IV) (IV) ,hydrogenating the imine (IV) to provide an amine of formula (V) (V) ,reacting the amine (V) with an acid chloride of formula (VI) Cl-(CH2)n-CO-Cl (VI) (in which n is as defined herein), to provide a chloride of formula (VII) (VII) ,reacting the chloride (VI) with a diamine of formula (VIII) H2N-(CH2)m-N(R)2 (VIII) (in which R and m are as defined herein), to provide a compound of formula (IX) (IX) reacting the compound (IX) with a chloroformate of formula R2-O-CO-Cl when Y is to be oxygen or with an isocyanate of formula R2-NCO when Y is to be = NH (in which formulae R2 is as defined herein) to provide a carbamate or urea derivative of formula (I), and if desired converting the derivative of formula (I) into an addition salt with a pharmaceutically acceptable acid.

2. A compound which is carbamate or urea derivative of general formula (I) (I) wherein X is hydrogen, halogen or methylthio, Y is oxygen or , R is C1-C4 alkyl, R1 is hydrogen, one or two halogen atoms or trifluoromethyl groups, a methyl group, a methoxy group, a cyano group, a nitro group, a methoxycarbonyl group, a methylenedioxy group linked to two adjacent carbon atoms of the benzene ring to which it is attached, or a fused benzo group forming an .alpha.-naphthyl or .beta.-naphthyl group with the benzene ring to which it is attached, R2 is a linear or branched C1-C8 alkyl or alkenyl group optionally substituted with halogen atoms or a methoxy group, a cyclopropylmethyl group, or a phenyl group optionally substituted with one or two halogen atoms or methyl groups, n is 1 or 2, and m is 2 or 3, or an addition salt thereof with a pharmacologically acceptable acid.

3. A product according to Claim 2, wherein n and m are each 2, and Y is oxygen.